The goal of this R24 application is to generate a panel of reliable pathogenic R5 SHIVs representing globally circulating HIV-1 strains, with emphasis on subtype C and CRF_AE that are fueling the HIV-1 pandemic. We envision that these novel SHIVs which recapitulate the immunopathogenesis of HIV in humans will serve as valuable resources not only as challenge viruses in preclinical nonhuman primate (NHP) studies to determine if vaccine-induced immunity has activities against multiple variants within a single genetic subtype as well as across subtypes, but to improve our understanding on the pathogenesis of the HIV-induced immunodeficiency to advance progress towards treatment, prevention and cure. The proposed project leverages the complementary expertise of Dr. Cheng-Mayer in SHIV models of AIDS and of Dr. Blanchard in nonhuman primate medicine, and builds on our documented experience in generating successful R5 SHIVs in HIV-1 vaccine and pathogenesis studies. In aim 1, we will characterize a recently obtained late-stage SHIVC isolate for its ability to transmit mucosally, maintain chronic viremia durably and induce disease consistently with development of giant cell encephalitis and coreceptor switching. In aim 2, we will construct three additional R5 SHIV molecular clones expressing Envs from transmitter/founder or early infection subtype C and CRF_01AE viruses. We will adapt and improve their replicative capacity in vivo by performing four rapid serial passages in Indian rhesus macaques, the most commonly used monkey species for AIDS research. Development of disease in the late passage macaques will be monitored. In aim 3, we will evaluate the suitability of swarm cell-free viruses recovered from the subtype C and CRF_AE SHIV passage macaques with disease as challenge viruses by assessing their mucosal transmissibility and ability to induce chronic viremia and immunodeficiency. We believe the potential impact of the resources is substantial. Resource applications include: (1) development of tools for AIDS vaccine research in NHPs; (2) development of tools for preclinical pre-exposure prophylaxis (PrEP), therapeutic and cure studies; (3) investigation of the interaction between HIV-1 subtype and the immune system during acute and chronic infection; (4) investigation of the impact of HIV-1 subtype on AIDS pathogenesis. We envision the R5 SHIVs and models generated will guide vaccine design and development, generate new hypotheses and experiments in AIDS pathogenesis to advance basic and translational discovery research, and facilitate preclinical research in HIV prevention, therapeutics and cure.